HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction

Abstract

BackgroundHIV-infected individuals are at increased risk for acute and chronic airway disease even though there is no evidence that the virus can infect the lung epithelium. Although HIV-related proteins including gp120 and Tat can directly cause oxidant stress and cellular dysfunction, their effects in the lung are unknown. The goal of this study was to determine the effects of HIV-1 transgene expression in rats on alveolar epithelial barrier function. Alveolar epithelial barrier function was assessed by determining lung liquid clearance in vivo and alveolar epithelial monolayer permeability in vitro. Oxidant stress in the alveolar space was determined by measuring the glutathione redox couple by high performance liquid chromatography, and the expression and membrane localization of key tight junction proteins were assessed. Finally, the direct effects of the HIV-related proteins gp120 and Tat on alveolar epithelial barrier formation and tight junction protein expression were determined.ResultsHIV-1 transgene expression caused oxidant stress within the alveolar space and impaired epithelial barrier function even though there was no evidence of overt inflammation within the airways. The expression and membrane localization of the tight junction proteins zonula occludens-1 and occludin were decreased in alveolar epithelial cells from HIV-1 transgenic rats. Further, treating alveolar epithelial monolayers from wild type rats in vitro with recombinant gp120 or Tat for 24 hours reproduced many of the effects on zonula occludens-1 and occludin expression and membrane localization.ConclusionTaken together, these data indicate that HIV-related proteins cause oxidant stress and alter the expression of critical tight junction proteins in the alveolar epithelium, resulting in barrier dysfunction.

Extracellular Matrix Influences Alveolar Epithelial Claudin Expression and Barrier Function

“…This is significant, because ZO-1 is critical for proper insertion of claudins into functional tight junction strands (7). Also, in an HIV transgenic rat model, we found that impaired alveolar barrier function correlated with decreased ZO-1 expression, consistent with an important role for ZO-1 in alveolar epithelial tight junctions (42). However, ZO-1 expression is not the sole determinant of epithelial barrier function, as cells cultured for 2 days on fibronectin formed a high-resistance monolayer, yet had lower ZO-1 content than Day 2 cells on laminin or type I collagen.…”

Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats

“…Male hemizygous NL4-3Δgag/pol Fischer 344 rats (HIV-1 Tg; Harlan) have been previously described in detail (18,20).…”

“…In this study we investigated the impact of HIV-1/AIDS on the skeleton, using HIV-1 transgenic (Tg) rats, an animal model of HIV-1/AIDS involving the global transgenic expression of a HIV-1 gag/pol deleted provirus (18). This model recapitulates many of the immunological and other metabolic complications associated with HIV-1/AIDS in humans, including wasting, skin lesions, cataracts, and pulmonary, immunological, neurological, cardiac, and renal pathologic processes (18)(19)(20). We now add osteoporosis to this list of complications, and validate the HIV-1 Tg rat for the study of the mechanisms underlying bone loss in HIV-1/AIDS.…”

HIV and Chronic Obstructive Pulmonary Disease: Is It Worse and Why?

“…Lung and plasma glutathione levels are lower in HIV-infected smokers than in HIV-infected nonsmokers (42,43). Recent studies demonstrated that, in a rat model, HIV transgene expression resulted in oxidant stress, and alterations in epithelial barrier function via altered expression of tight junction proteins (44). The impact of antiretroviral therapy on oxidative stress is unclear (45,46).…”